Hrup643 201.215

Human Reproduction Update, Vol.8, No.3 pp. 201±215, 2002 Hormone replacement therapy and the prevention of Helena J.TeedeAddress for correspondence: Monash University Department of Medicine, Vascular Medicine and Sciences Unit, Dandenong Hospital, David St, Dandenong 3175, Victoria, Australia. E-mail: Cardiovascular disease (CVD) is the primary killer of both men and women in Western societies. The implementation of preventive strategies has led to a fall in the rate of CVD, but there is still much to be achieved. Proven interventional strategies are largely under-utilized, and the search continues for further promising interventions. HRT appears to reduce CVD in post-menopausal women, based on observational data supported by plethora of evidence for the bene®cial cardiovascular effects of estrogen. However, a recent controlled trial in post- menopausal women with established CVD has shown that a speci®c combined oral HRT regimen did not reduce, and may even contribute to, an early increase in cardiovascular events, suggesting that HRT is inappropriate in secondary prevention. HRT may be useful in the primary prevention of CVD, yet observational data that suggested cardiovascular bene®t with HRT also suggests that 80% of CVD in women could be eliminated by lifestyle modi®cation, without the attendant risks of HRT including thrombosis and (potentially) breast cancer. At present, it is arguable that the evidence is inadequate to recommend HRT solely for the purpose of CVD prevention, and that the challenge for the health professional should be appropriate utilization of established preventative therapies, with further research into the potential role of HRT and estrogen-receptor modulators.
Key words: cardiovascular disease/health management/hormone replacement therapy/lifestyle modi®cation/preventative therapy Lifestyle modi®cations are well known to reduce CVD with few side effects and many other health bene®ts. Many pharmacological interventions including anti-platelet, anti-hyper- Cardiovascular disease in women, and established risk factors tensive and lipid-lowering therapies also reduce cardiovascular morbidity and mortality (Yusef, 1998). Increasing evidence suggests that the targets for cardiovascular risk factor reduction should be more aggressive. Yet it appears that even existing Randomized controlled human interventional data targets are not being met (Mosca et al., 1999; Wood, and the Joint European Task Force, 2001). The recent American Heart Association guidelines on preventive cardiology noted that clinicians are missing opportunities for prevention, and that this is especially the case in women (Mosca et al., 1999).
Women spend on average 35 years of their lives in a post- menopausal, low-estrogen state. It is during these years that the majority of CVD burden is noted. In this setting, hormone Cardiovascular disease (CVD) is the number one killer in both replacement therapy (HRT) may have a role to play in the men and women in Western society. The disease process is prevention of CVD. There is overwhelming observational data to largely attributed to age and lifestyle factors (Stampfer et al., support a bene®cial effect of HRT on the cardiovascular system.
2000). Effective health management strategies, if appropriately There are, however, limitations in the application of observational implemented, have the potential for signi®cant impact on both data to the clinical setting. A wealth of animal and human mortality and morbidity. With the emphasis on evidence-based interventional data, focusing on isolated mechanisms of estrogen medicine, the ef®cacy of preventive measures has been proven in action, has suggested largely bene®cial cardiovascular effects.
numerous well-designed trials (Yusef, 1998). As a result, the Yet, the translation of animal data to the post-menopausal woman implementation of these preventive measures has resulted in a may not be valid. Furthermore, the in-vivo effects of estrogen are recent fall in the incidence of CVD (Hu et al., 2000).
ubiquitous and complex. In this setting it is the net effects of Ó European Society of Human Reproduction and Embryology estrogen rather than isolated estrogenic mechanisms that are most progression to diabetes, in those with impaired glucose tolerance relevant clinically (Teede and McGrath, 1999). This can only be (Hu et al., 2000, 2001; Tuomilehto et al., 2001). Unfortunately, assessed in controlled human trials focusing on de®nitive clinical obesity is increasing in Western societies, and may be slowing the end-points. In limited controlled data completed to date, the decline in CVD (Hu et al., 2000). This is likely to be contributed effects of HRT appear to be neutral or even deleterious (Hulley et to by the sedentary nature of Western lifestyle. Although evidence al., 1998). Estrogen actions depend on dose, type, route of is largely observational, the role of exercise in the prevention of administration and on the co-administered progestin. Therefore, CVD is also well accepted. The National Heart Foundation of even the results of controlled trials should be interpreted only for Australia and the American Heart Association recognize physical the speci®c HRT preparations used and the populations studied.
inactivity as an independent risk factor, and recommend 30 In considering the potential role for HRT in CVD prevention, minutes of moderate intensity exercise ®ve times per week. Few clinicians need to appreciate the dif®culties in translating existing people achieve these targets, however (Glassberg and Balady, data on the vascular effects of HRT into clinical practice. There is also a need to interpret all results in the era of evidence-based Improving lipid pro®les in those with established CVD has medicine and in the setting of inadequate utilization of existing been shown to lead to regression of atherosclerosis and markedly proven preventive therapies (Burger and Teede 2001; Mosca et to reduce cardiovascular events (Ades, 2001). In women, low al., 2001a; Wood, and the Joint European Task Force, 2001).
serum high-density lipoprotein (HDL) and raised triglycerides Future research is essential to resolve many important issues prior appear more important than low-density lipoprotein (LDL) levels to establishing de®nitively the role of HRT and other estrogenic alone. However, lipid-lowering trials have demonstrated that high-risk women bene®t from LDL lowering with statins, for both primary and secondary prevention, as much as men (Heart Cardiovascular disease in women, and established risk Protection Study Collaboration Group, 2001). Improvement in lipid pro®les is achievable through dietary modi®cation, exercise and drug therapy; the latter approach has been proven to be Coronary heart disease is the leading cause of mortality, and especially effective. In the secondary prevention `4S' trial contributes to signi®cant morbidity among women in western (Scandinavian Simvastatin Survival Study Group, 1994), cardio- society (Mosca et al., 1999; Tsang et al., 2000). In fact, in women vascular events were reduced with statins by 30%. In the it causes more deaths than the next 14 most common fatal conditions combined (Tsang et al., 2000). It has been estimated secondary prevention `CARE' trial, even those with lower LDL from the prospective Nurses Health Study that the majority of serum levels had a 24% reduction in coronary events (Sacks et al., CVD is preventable by modi®cation in lifestyle (Stampfer et al., 1996). In those with low HDL levels, treatment with ®brates 2000), and comprehensive risk reduction is a well-established resulted in a 22% reduction in relative risk of non-fatal approach to prevent the condition. Proven preventive strategies myocardial infarction (Rubins et al., 1999). Despite the ef®cacy encompass exercise, nutritional modi®cation, weight loss and of these intervention strategies, recent data have suggested that cessation of smoking, all of which carry no health risks (Ades, the ideal cholesterol targets are reached in only one-third of 2001). Additional bene®cial strategies include targeted therapy to patients with coronary disease (Ades, 2001).
reduce blood pressure, improve lipid pro®les, control diabetes, Intensive blood pressure control is well established for the reduce platelet adhesion and modulate the neurohumoral system primary and secondary prevention of cardiovascular disease. The (Scandanavian Simvastatin Survival Study Group, 1994; `HOT' study noted that the lower the blood pressure, the lower the Hennekens et al., 1997; Anonymous, 1998; Hansson et al., risk of vascular events (Hansson et al., 1998). The targets for 1998; Progress Collaborative Group, 2001).
optimal blood pressure control are being lowered progressively.
Cessation of smoking is associated with a reduction in coronary Currently, blood pressures of <140/90 mmHg are being events. In subjects who have suffered a myocardial infarction, a recommended, with <130/85 mmHg in high-risk groups (World 50% reduction in mortality and reinfarction rate has been noted Health Organization, 1999). However, despite the overwhelming one year after cessation (Wilson et al., 2000). Public health evidence for blood pressure lowering, the accepted targets are not campaigns aimed at smoking cessation have been successful; for being met in the majority of subjects (Wood, and the European example, in Australia intensive public health measures have led to a decline in smoking rates down to 20% of the population, though Diabetes is an important risk factor in women, with the risk of further effort is still required to minimize the impact of smoking CVD increased 3- to 7-fold compared with 2- to 3-fold in men.
The Nurses Health Study suggested that diabetic women have a 5- Adherence to a healthy diet, weight loss and dietary change fold increase in coronary heart disease compared with non- including modi®cation in dietary fat intake appear to have diabetic women (Manson et al., 1991). Diabetic women have substantial bene®ts in CVD prevention (Stampfer et al., 2000; more severe CVD, higher CVD-related mortality and poorer Hooper et al., 2001; Tuomilehto et al., 2001). In a recent prognosis overall compared with non-diabetic women (Lowel et Cochrane Database Systematic Review focusing on the cardio- al., 2000; Friday, 2001). Although blood glucose control may play vascular effects of dietary fat modi®cation, it was noted that a role in the prevention of CVD (Anonymous, 1998), it is dietary intervention for more than 2 years showed signi®cant accepted that, in diabetic subjects, it is the other risk factors which reductions in the rate of cardiovascular events (Hooper et al., largely contribute to the burden of macrovascular disease (Friday, 2001). Dietary intervention appears to improve lipid pro®les, 2001). Thus, the presence of diabetes should target this high-risk lower blood pressure, reduce insulin resistance and slow population for aggressive preventive therapy.
Other important interventions that have a well-established role Progestins regulate the growth, differentiation and function in the secondary prevention of CVD include aspirin therapy (ISIS of target tissues primarily within the reproductive system.
Collaborative Group, 1988; Gaziano et al., 2000). Inadequate Progesterone is produced primarily by the dominant follicles utilization is still problematic however (Rogers et al., 1994; following ovulation, with levels falling signi®cantly once the Hennekens et al., 1997), as even in study settings such as the ovarian follicle pool is deplete and menopause occurs (Teede and secondary prevention `HERS' study, only 78% of women with Burger, 1998). In post-menopausal women, progestins are used established CVD received aspirin therapy (Hulley et al., 1998).
therapeutically to oppose the proliferative effects of estrogens on Neurohormonal modulation of the cardiovascular system with the endometrium and protect against endometrial malignancy beta blockade and angiotensin-converting enzyme inhibitors has (Beresford et al., 1997). Progesterone is the only natural form, but also been shown to have a role in the prevention of CVD its therapeutic use is limited by reduced oral bioavailability. The (Hjalmarson et al., 1981; Progress Collaborative Group, 2001).
majority of therapeutic progestins are therefore synthetic Despite the established ef®cacy of these strategies, smoking progestins; these are subdivided into those related structurally to rates are declining more slowly in women, obesity is increasing, either progesterone or testosterone (Whitehead, 1994). The and physical inactivity is escalating. In the USA, 50% of women different synthetic progestins also have variable pharmacokinetics aged >45 years have hypertension, and 40% aged >55 years have and biological activity with additional complex and diverse elevated cholesterol (Mosca et al., 1999). The under-utilization of effects outside the reproductive system.
preventive strategies may be related to women's misconceptions that they are more likely to die of breast cancer, or that heart Mechanisms of action: estrogen receptors (ER) and progesterone disease predominantly affects males (Giardina, 2000; Mosca et al., 2000). This highlights the need for further public health ER and PR are members of a superfamily of related proteins that measures and education. The attitude and role of the health mediate the nuclear effects of steroid hormones (Baysal and professional is pivotal in the promotion of both appropriate Losordo, 1996; Mendelsohn and Karas, 1999). These intracellular prevention strategies and treatments for established CVD. Current receptors function as ligand-activated transcriptional factors, evidence suggests that neither prevention nor treatment is regulating the synthesis of speci®c RNAs and proteins (Baysal optimal, especially in women (Rosano et al., 1993; Mosca et and Losordo, 1996). They are characterized by a large and complex ligand-binding domain, a DNA-binding domain (which is highly conserved) and a hypervariable regionÐthe amino- terminal region (Katzenellenbogen, 1996).
Estrogen actions are largely mediated by the ER, although non- Observational studies have long suggested that in post-menopau- genomic effects have been documented (Mendelsohn and Karas, sal women, estrogen combined with progestin may have a role in 1999). The diversity of action of different estrogenic compounds the prevention of CVD (Wolf et al., 1991; Grady et al., 1992; or ligands can be attributed to the complex ER system. Estrogenic Grodstein and Stampfer, 1995). These observations have been receptor activity is not dependent on steroidal con®gurations supported by interventional studies focusing on the isolated (Davies, 1998; Stanczyk, 1998), with both steroidal and non- mechanisms of sex steroid action within the vasculature. These steroidal compounds having estrogenic activity. Binding af®nity mechanisms are ubiquitous and are affected by the dose, type and does not directly translate to functional estrogenic activity, so the route of administered estrogen, as well as the co-administered true `biological estrogenicity' of a compound cannot be studied progestin. Appropriate interpretation of the vascular effects of directly (Kuiper et al., 1998; Anderson, 2000). This complexity of HRT requires an appreciation of the diversity and complexity of the system re¯ects many factors including the subtype and distribution of the ER (Kuiper et al., 1997; Makela et al., 1999; Mendelsohn and Karas, 1999). There are two known ER isoforms, ERa and ERb (Kuiper et al., 1997). ERs combined with different Estrogens regulate the growth, differentiation and function of estrogenic compounds can have different ligand-dependent diverse target tissues, both within and outside the reproductive conformational changes. This is by virtue of the ER subtype, system. There are three primary natural circulating estrogens: the presence of a variety of co-activators and co-repressors, and estradiol, estriol and estrone sulphate (converted in the periphery the cell and tissue type (Mendelsohn and Karas, 1999). It has been from estrone and estradiol) (Stanczyk, 1998). Follicle numbers hypothesized that the complexity of this system may facilitate fall as menopause approaches (Richardson et al., 1987), and when selective targeting of ERb, potentially inducing cardiovascular follicles are deplete at menopause the estradiol levels fall by effects without adverse stimulation of the reproductive tissues around 90% compared with reproductive levels (Teede and Burger, 1998). Estrogen replacement, in the form of HRT, can be There are also two isoforms of PR: hPR-A and hPR-B. The PR used therapeutically in post-menopausal women, and a wide has important interrelationships with the ER system, and variety of estrogens is available including the natural estrogens modulates biological responses (Baysal and Losordo, 1996).
(e.g. estradiol), synthetic estrogens (e.g. ethinylestradiol) and PRs combined with ligand can suppress ER activity; this is conjugated equine estrogens (CEE) (Anderson, 2000). The in¯uenced by the PR isoform, the ligand, the promotors and the pharmacokinetics and potency of these estrogens vary signi®- cell type (Katzenellenbogen, 1996). Cross-talk occurs between cantly based on the type of hormone and the route of ER and PR signalling systems in the modulation of biological administration, potentially contributing to signi®cantly different responses (Katzenellenbogen, 1996). The complexity of effects of observed clinical effects (Anderson, 2000).
the different progestins are likely to re¯ect their structural divergence from natural progestins, rendering their hormonal CVD in ever-users of HRT compared with non-users at 0.65 [95% effects more complex with variable androgenic and estrogenic con®dence interval (CI) 0.59±0.71] (Grady et al., 1992) and 0.64 (95% CI 0.59±0.68) (Grodstein and Stampfer, 1995). The relative The complexity of the sex steroid receptor system and the risk in current users was estimated at 0.5 (95% CI 0.45±0.59) variety of different estrogenic compounds and progestins used in (Grodstein and Stampfer, 1995). Although the observational data clinical practice render the interpretation of existing literature are almost unanimous, a recent observational study in women very dif®cult. Ideally, each study needs to be interpreted with established vascular disease and unstable angina has individually, and the ®ndings attributed only to the speci®c suggested a deleterious effect of HRT. In this study, increased preparations, combinations, doses and routes of administration events were noted in those initiated on HRT after acute used for each given tissue end-point and each species studied.
myocardial infarction (Alexander et al., 2001).
Inherent in the design of all observational studies is the problem of bias, and there are important caveats that must be applied when interpreting these data. First, most of these studies HRT has been utilized to treat post-menopausal women for over compared women who had elected to take HRT with women who 50 years. The bene®ts of HRT include the amelioration of had either not considered it or elected not to take it (Barrett- menopausal symptoms, and an improvement in the quality of life.
Connor, 1991). Even in socioeconomically homogeneous pop- However, HRT has been increasingly prescribed for potential ulations, these two groups of women differ. Women who elect to long-term indications including protection against bone loss, take HRT tend to be better educated, exercise more, have lower urogenital atrophy and prevention of CVD (MacLennan et al., blood pressure and better lipid pro®les and are more likely to 1999). Questions remain about the effectiveness of HRT for long- participate in preventive health measures than women who do not term indications, especially cardiovascular disease prevention take HRT (Barrett-Connor, 1991; Matthews et al., 1996). HRT (Mosca, 2000, 2001; Mosca et al., 2001a). The clinical users may therefore be at lower risk of CVD compared with non- advantages of therapy remain to be proven, and the potential users even before starting HRT (the `healthy user effect').
disadvantages also need to be clari®ed, including the indication Adjustment for known confounding variables has little effect on from epidemiological studies that the incidence of breast cancer the estimated relative risk of CVD. It does seem likely though that may be increased with post-menopausal estrogen use.
the healthy user effect would not account for all of the 35±50% reduction in CVD risk (Bush et al., 1987). Indeed, many of these biases are less notable in the large cohort study, The Nurses Health Study, where 70 533 nurses have been followed for 20 years. Those on HRT still have a lower risk of CVD compared A protective role of estrogen in CVD in post-menopausal women with non-users (Grodstein et al., 1996, 2000). Nonetheless, has been suggested by the low risk of CVD among premenopausal confounding variables (recognized and unrecognized) may have women and a narrowing of the gender gap after menopause. The led to an overestimate of the magnitude of HRT reduction in CVD suggestion that endogenous estrogen maybe cardioprotective was Second, most women in reported studies were taking supported by observational data suggesting lower CVD risk in unopposed estrogen, rather than combined estrogen-progestin, women on HRT as opposed to non-users (Grady et al., 1992). The as is now prescribed for women with an intact uterus (Beresford et assumption that exogenous HRT lowers CVD risk is primarily al., 1997). Progestins may negate some of the cardiovascular based on observational data, although supportive mechanistic effects of estrogens. The apparent opposing effects of progestins interventional studies suggest bene®cial cardiovascular actions of has been reviewed (Sitruk-Ware, 2001). In mechanistic studies, estrogen. In contrast, human controlled trials of HRT focusing on modulation of the effects of estrogen on plasma lipids, arterial clinical cardiovascular end-points in both men and women have dilatation, blood ¯ow and ultimately atherosclerosis have all been failed to con®rm any bene®t. De®nitively, two large controlled noted (Adams et al., 1997; Sitruk-Ware, 2001). Limited available primary prevention studies in post-menopausal women are now human observational data based on combined estrogen and underway to address both the risks and bene®ts of HRT, and these progestin use suggest that this effect may not be substantial results are awaited with great interest. In the interim, a (Falkeborn et al., 1992; Psaty et al., 1994; Grodstein et al., 1996), comprehensive review of the literature is presented herein.
although the type and regimen of progestin used may also be Extensive cohort and case±control studies have focused on the relevant (Adams et al., 1990, 1997; Anonymous, 1995).
in¯uence of HRT on a range of cardiovascular end-points including death, myocardial infarction, angiographic coronary Proposed mechanisms of the cardioprotective effects of estrogen stenosis grades and angioplasty and bypass grafting rates (Wolf et Multiple mechanisms have been proposed to account for the al., 1991; Grodstein and Stampfer, 1995; Grodstein et al., 1996, apparent protective effects of estrogen against coronary artery 1997, 2000; Sullivan et al., 1997, 1998). The studies vary considerably in their end-points and design, and also in the methods used to eliminate the effects of confounding variables.
Most studies have suggested a 40±50% reduction in cardiovas- The primary proposed mechanisms of bene®cial estrogen action cular disease in HRT users compared with non-users (Wolf et al., on the cardiovascular system are the effects on lipid metabolism 1991; Grodstein and Stampfer, 1995; Grodstein et al., 1996, (Godsland, 2001). Oral estrogen treatment reduces plasma total 1997). Two meta-analyses have estimated the relative risk of and LDL-cholesterol by 5±15%, increases HDL-cholesterol by Table I. Proposed mechanisms of estrogen action on the cardiovascular Progestins tend to lower HDL concentrations, and this partially antagonizes the favourable effects of estrogen (Anonymous, 1994, 1995). The more androgenic progestins have a greater deleterious effect on HDL (Crook et al., 1992; Anonymous, 1995; Hart et al., 1998; Godsland, 2001). The least deleterious effects are observed with dydrogesterone, progesterone and cyproterone acetate (Godsland, 2001). Pending further clari®cation of the clinical relevance of combined estrogen and progestin-induced lipid changes, statins should be ®rst-line therapy for hypercholester- olaemic women. However, women who require estrogen for other indications may derive further lipid bene®ts, and in theory the Reduced proliferation after endothelial injury selection of less androgenic progestins may be more appropriate The changes in vasoreactivity observed with estrogen have been partly attributed to increased nitric oxide (NO) production.
Animal studies have noted gender-speci®c differences in the NO pathway, with NO release being greater in females, whilst a lower basal vasomotor tone and less responsiveness to vasocon- strictors has been noted compared with males (Hayashi et al., 1992; Binko et al., 1998). Exogenous estrogen increases the expression of nitric oxide synthase (NOS) in both animals 10%, and reduces lipoprotein Lp(a) concentrations (resistant to (Weiner et al., 1994) and humans (Hishikawa et al., 1995).
conventional lipid-lowering therapy) (Anonymous, 1995; Darling Furthermore, estrogen produces relaxation of vascular smooth et al., 1997; Godsland, 2001). The effect on HDL may be muscle by a NO-dependent process (Darkow et al., 1997).
especially important, as low plasma HDL is a strong predictor of Interestingly though, estrogen does not activate downstream cardiovascular mortality in women. Estrogen also inhibits mediators in the NO pathway, including the primary effector oxidation of LDL (Sack et al., 1994), which may render them molecule protein kinase G (Teede et al., 2001b). However, less atherogenic. A possible unfavourable effect of estrogen is an production of the potent vasodilator NO may be cardioprotective increase (20±25%) in plasma triglyceride concentrations as it not only regulates blood ¯ow but also inhibits platelet (Anonymous, 1995; Darling et al., 1997; Godsland, 2001), as aggregation at the level of the endothelium (Ignarro, 1989).
Endothelin-1 is the most potent of the vasoconstrictor high triglyceride levels are also predictors of cardiovascular hormones. Females have lower endothelin levels, especially when mortality in women. In contrast to oral estrogens, the effects of pregnant. Trans-sexuals receiving estrogen have been noted to transdermal estrogen preparations on serum lipids are either have a fall in endothelin-1 levels (Polderman et al., 1993). A minimal (Crook et al., 1992) or absent (Lufkin et al., 1992; recent review based on randomized, controlled studies of HRT on Modena et al., 1999; Teede et al., 2001d). This is thought to be the cardiovascular system in post-menopausal women concluded related to the fact that it is not orally absorbed and therefore does that HRT reduced endothelin levels (van Baal et al., 2000).
not cause an acute increase in concentrations within the liverÐthe Potentially, this reduction may also improve vascular tone It has been estimated that lipid changes resulting from oral The direct assessment of the effects of sex steroids on arterial HRT use may only account for 25±50% of the reduction in CVD blood ¯ow, arterial resistance and vessel diameter has been in observational studies (Bush et al., 1987). Unlike statins, studied extensively (Reis et al., 1994). Most studies have controlled trials are limited and the clinical signi®cance of HRT- determined endothelial dependence of the artery or vascular induced lipid changes is not well characterized. In the secondary territory in question by examining responses to acetylcholine.
prevention HERS trial, lipid bene®ts were observed, yet reduction Invasive vascular reactivity studies have demonstrated that in CVD events was not noted (Hulley et al., 1998).
atherosclerotic arteries exhibit a reduced response to acetylcho- The clinical relevance of the HRT-induced lowering of Lp(a) line administration, which is reversed by estrogen addition in the also needs clari®cation, as the pathophysiological signi®cance of monkey model (Williams et al., 1990). Non-invasive studies of this complex polymorphic lipoprotein particle remains unclear endothelial function using ultrasound techniques including ¯ow- (Marcova and Koschinsky, 1999; Godsland, 2001). Interestingly, mediated vasodilation have been contradictory. Observational and a recent HERS study subgroup analysis suggested that Lp(a) was short-term estrogen studies have suggested bene®t, whilst long- an independent risk factor for recurrent coronary heart disease in term controlled trials have not necessarily supported these results post-menopausal women, and that treatment with estrogen and (McCrohon et al., 1996; Sorensen et al., 1997; Teede et al., progestin lowered Lp(a) levels. It also demonstrated that among women with a high baseline Lp(a) level, those on HRT had a Studies in post-menopausal women have suggested that lower rate of cardiovascular events compared with those with estrogen therapy may have anti-ischaemic effects in women with lower baseline Lp(a) (Shlipak et al., 2000).
established CVD. A controlled trial in 74 post-menopausal women with stable angina showed that HRT increased the time to estrogen-mediated inhibition of the migration and replication of ST depression and total exercise duration compared with placebo smooth muscle cells in vitro (Makela et al., 1999). In the rabbit, therapy (Sanderson et al., 2001). This ®nding supported the rat and mouse, intimal thickening after mechanical carotid results of a previous uncontrolled trial (Rosano et al., 1997).
balloon injury appears to be reduced by estrogen pretreatment, this being mediated by inhibition of vascular smooth muscle Atherosclerosis and vascular structural changes proliferation (Foegh et al., 1994; Sullivan et al., 1995; Oparil et The effect of HRT on atherosclerosis is perhaps best appreciated al., 1997). Interestingly, progestin (MPA) blocked the effects of from an extensive series of experiments in the cynomolgus estrogen in this model (Oparil et al., 1997). When given alone, monkey atherosclerosis model (Clarkson, 1994; Clarkson et al., MPA enhanced the neointimal response to balloon injury in intact 1995, 2001). Monkeys were oophorectomized, and then rando- females, presumably by blocking productionÐand thus the mized to placebo, oral or transdermal estrogen alone, combined vasoprotective effectÐof endogenous estrogen. However, when HRT with continuous or cyclic progestin or tibolone. They were given in combination with exogenous estrogen, MPA negated the fed an atherogenic diet for 2 years, after which (at necropsy) a bene®cial reduction in neointimal proliferation with estrogen comprehensive assessment of coronary atherosclerosis was alone (Oparil et al., 1997). Estrogen has also been shown to undertaken (Clarkson, 1994; Clarkson et al., 1995, 2001).
facilitate the re-endothelialization of the carotid artery after Estrogen alone reduced the cholesteryl ester content (Wagner et balloon injury (White et al., 1997). Furthermore, in vitro estrogen al., 1997) and the atherosclerotic plaque by either 50% inhibits vascular smooth muscle cell proliferationÐan effect that (transdermal therapy) or 70% (oral therapy) compared with those is directly mediated by the ER (Baysal and Losordo, 1996).
animals receiving placebo (Clarkson et al., 1995). Studies in atherosclerosis models in other species, including rabbits, have also suggested that estrogen provides protection against athero- Thrombosis is an important component of arterial vascular events sclerosis (Brehme et al., 1999). It should be noted, however, that as well as venous thromboembolic events (VTE). Previously, debate persists as to whether animal models of atheroma, induced arterial cardiovascular events were attributed to progressive solely by an atherogenic diet, actually provide a true model of obstruction from atherosclerotic plaques, though this concept has been revised as it has become clear that cardiovascular events The effects of additional progestins on atherosclerosis in are characterized by an acute obstructive process superimposed animal models are less clear. In the cynomolgus monkey, natural on a previously mild to moderate single atherosclerotic lesion progesterone or cyclic medroxyprogesterone acetate (MPA) did (Theroux and Cairns, 1998). Subsequent morphological analysis not appear to in¯uence the bene®cial effects of estrogen on has revealed plaque disruption and intraluminal thrombi (Ross, atherosclerosis (Adams et al., 1990). However, the effects of 1993). Indeed, coronary thrombosis was noted on underlying continuous MPA in this model were con¯icting. Some studies ruptured plaque in 95% of those suffering sudden cardiovascular suggested that continuous MPA negated the bene®cial effects of death (Davies and Thomas, 1984). Accordingly, the mainstay of estrogen, including reduced atherosclerosis, aortic connective acute treatment of acute myocardial infarction is now thrombo- tissue remodelling after lipid lowering and a reduction in lytic therapy aimed at dissolving the occluding thrombus and dobutamine-induced myocardial ischaemia (Adams et al., 1997; reperfusing the ischaemic myocardium (ISIS Collaborative Register et al., 1998; Williams et al., 2002). However, in a recent Group, 1992). Moreover, simple measures including aspirin and study in the same monkey model, continuous MPA did not affect heparin therapy have proven useful in both the treatment and the bene®cial reduction in atherosclerosis seen with estrogen prevention of clinical events (Hansson et al., 1998; Gaziano et al., (Clarkson et al., 2001). In rabbits, coronary ¯ow rates were 2000). Furthermore, in¯ammatory changes within atherosclerotic increased with estrogen therapyÐan effect not observed when plaque appear to increase vulnerability to rupture, leading to estrogen was combined with several types of progestin, including thrombus formation, myocardial ischaemia and clinically overt MPA (Gorodeski et al., 1998). The atherosclerotic effects of disease. In this setting an intervention which is pro-in¯ammatory combining speci®c progestins with estrogen are not yet clari®ed, and procoagulant, potentially may increase arterial thrombosis and therefore also clinical cardiovascular events.
Interestingly, it was noted (Hanke et al., 1999) that estrogen Concerns have been raised about the prothrombotic effects of could inhibit the progression of atherosclerosis in rabbits when estrogen, with an increase in both VTE and potentially also only mild or moderate vessel wall abnormalities were present, but arterial events (Coronary Drug Project Research Group, 1970; appeared unable to do so once severe atherosclerotic disease was Hulley et al., 1998; Hoibraaten et al., 2000, 2001; Teede et al., established. The anti-atherosclerotic effects of estrogen were 2000a; Alexander et al., 2001; Peverill et al., 2001). In controlled apparently mediated by the endothelium, which becomes trials, HRT increased the risk of VTE by 3- to 4-fold, with the dysfunctional once atherosclerosis develops. This is supported increase noted in the early 1±2 years of treatment (Figure 1) by studies in the monkey model where the bene®cial effect of (Hulley et al., 1998; Hoibraaten et al., 2000). This increase estrogen on acetylcholine-mediated vasodilation only occurred in appeared to be independent of, and multiplicative with, other segments of the coronary artery where mild atherosclerosis was prothrombotic risk factors (Lowe et al., 2000).
present. No effects were noted in arterial segments with severe It has also been proposed that the prothrombotic effect of HRT atherosclerosis, suggesting that estrogen may not be useful in may have been responsible for the early increase in thrombotic secondary prevention (Clarkson, 1994).
arterial cardiovascular events observed in the secondary preven- In a rat model of carotid injury, vascular ERb receptors were tion of cardiovascular disease, the HERS study (Hulley et al., up-regulated, and this was accompanied by a dose-dependent, 1998), though this has yet to be clari®ed. A population-based Additional effectsA plethora of additional mechanisms of HRT action on the vascular system has been demonstrated, including effects on ion channels, membrane receptor aggregation and changes in protein phosphorylation status (Mendelsohn and Karas, 1999; Pines et al., 1999; Stefano et al., 2000). Other estrogen effects include changes in the renin±angiotensin system (Proudler et al., 1995) and bene®cial changes in carbohydrate metabolism and body fat distribution (Barrett-Connor et al., 1989). A recent review based on randomized, controlled studies of HRT on the cardiovascular system in post-menopausal women also concluded that HRT reduced homocysteine levels (van Baal et al., 2000).
Whilst individual mechanisms of estrogen action are of interest, Figure 1. Cardiovascular (CV) outcomes by treatment group and year since the mosaic of data available on the cardiovascular effects of sex randomization in the `HERS' study (Hulley et al., 1998). AMI = acute hormones is complex and in¯uenced by a variety of factors, myocardial infarction; DVT = deep vein thrombosis.
including natural versus synthetic hormones, species, age, hormonal status, which vessel is studied, baseline endothelial case±control study has demonstrated that in hypertensive women function, arterial structure, lipid and coagulation factors.
with a ®rst non-fatal acute myocardial infarction (AMI), there was Furthermore, it remains controversial as to whether there is a a positive association between genetic thrombophilia, HRT use true animal model for atherosclerosis as the models used to date and AMI (Psaty et al., 2001). Overall, the concern is that the have atherosclerosis induced by very high levels of cholesterol procoagulant effects of HRT may negate the cardiovascular intake without other co-existent risk factors. Therefore, despite this wealth of data it remains dif®cult to assess the effect of HRT In mechanistic studies based on the use of accurate immuno- on the vascular system (Teede and McGrath, 1999).
diagnostic haemostatic markers, HRT appears primarily to activate coagulation, and although it increases ®brinolytic potential this may only be a secondary physiological response Randomized controlled human interventional data to the up-regulation noted in coagulation (Teede et al., 2000; Although the extensive data on the in¯uence of HRT on vascular Hoibraaten et al., 2001). Although the mechanism of estrogen- disease in both human and animal studies appear positive, the induced up-regulation of coagulation remains unknown, in picture portrayed in the randomized trials on the effects of HRT controlled trials HRT has been shown to reduce the vital tissue on cardiovascular disease suggests that HRT may not be factor pathway inhibitor (TFPI), along with a reduction in other bene®cial, but rather have a neutral effect or even increase the endogenous anticoagulants (Peverill et al., 2001; Hoibraaten et al., 2001). Potentially, this may allow up-regulation of the Early data were available from the 1960s with the randomized coagulation cascade. Tissue factor is the principal initiator of the Coronary Drug Project (CDP) involving over 7500 male subjects extrinsic coagulation pathway, and the fall in TFPI has been with documented myocardial infarction (Coronary Drug Project directly correlated to the degree of coagulation activation noted Research Group, 1970). This project was stopped prematurely as with HRT (Hoibraaten et al., 2001). The effects on platelets may no bene®ts of estrogen were observed. However, a higher rate of be neutral (Teede et al., 2001), though further research is required venous thrombosis was observed, and in a recent reanalysis of the CDP data a signi®cant increase in coronary heart disease within As noted, the pathophysiology of an acute arterial ischaemic the ®rst 4 months of treatment was demonstrated (Mosca, 2001).
event includes plaque rupture and subsequent thrombosis. At Recently, a substantial human study on the effects of HRT on present, there is no available test that will predict which plaques vascular disease in women, the `HERS' study, was reported are vulnerable to rupture, occurring in the setting of an (Hulley et al., 1998). This was a well-designed, double-blind, in¯ammatory process within the plaque. C-reactive protein placebo-controlled, randomized study of combined continuous (CRP) has been noted to be an independent cardiovascular risk oral HRT (0.625 mg conjugated equine estrogen + 5 mg medroxy factor (Koenig, 2001), though as yet it has not been ascertained progesterone acetate) use in the secondary prevention of vascular whether CRP is a marker or is truly pathogenic in the disease, in 2763 post-menopausal women of mean age 66.7 years, in¯ammatory process, or whether modulation of CRP will alter with pre-existing coronary atherosclerotic disease over 4.1 years.
the disease process (Koenig, 2001). HRT has been documented to The study failed to demonstrate any overall difference in vascular increase CRP plasma levels (Ridker et al., 1999; Walsh et al., events, including myocardial infarction, coronary revasculariza- 2000), potentially increasing the risk of plaque rupture. In contrast tion, unstable angina, congestive cardiac failure, stroke, transient to these results, reductions in circulating levels of the in¯amma- ischaemic attack or peripheral arterial disease, between the tory markers E-selectin, vascular cell adhesion molecule (V- placebo and active treatment groups. This was despite an CAM) and intracellular adhesion molecule (I-CAM), which may improvement in lipid parameters in those patients receiving also re¯ect plaque stability, have been noted with HRT (van Baal HRT (Hulley et al., 1998). The arterial vascular event rate in the et al., 1999, 2000). However, again the net clinical signi®cance of ®rst year was actually signi®cantly increased [relative risk these ®ndings has yet to be established.
(RR) = 1.52], falling over time to a RR of 0.67 by the fourth year (Figure 1). The trend towards a fall in the cardiovascular compared estradiol + monthly gestodene, estradiol + 3-monthly event rate over the 4 years was signi®cant, yet overall, no gestodene, or a control group on no HRT. In 321 healthy post- differences were noted between the active and placebo groups menopausal women with increased IMT (representing early subclinical atherosclerosis), one year of HRT did not slow IMT On the basis of previously published data, these results were progression despite falls in LDL-cholesterol levels (Angerer et unexpected. Clinically signi®cant effects of HRT on the al., 2001). However, a more recent study in 222 post-menopausal haemostatic system were con®rmed, with an increase in venous women without pre-existing CVD compared unopposed estrogen thrombosis similar to that seen with the oral contraceptive pill with placebo therapy with and without lipid-lowering agents over (Hulley et al., 1998). A two-edged sword effect of HRT was 2 years. The rate of progression of subclinical atherosclerosis proposed, with the authors theorising that the prothrombotic (IMT) was lower in those patients randomized to unopposed effects of estrogen may negate any possible atherosclerotic estradiol compared with placebo, although a signi®cant effect of bene®ts in women with established cardiovascular disease and estradiol was only noted in those women not receiving lipid- pre-existing plaques, which are prone to rupture, though this has lowering therapy (Hodis et al., 2001). The women in the latter study did not have pre-existing CVD, and were studied for longer The criticisms of the HERS study were related primarily to the compared with the previously described investigation (Angerer et progestin regimens used (continuous medroxy progesterone acetate, shown in some animal studies to negate the bene®cial A pooled study which was published in 2000, analysed data effects of estrogen, yet not in others) (Adams et al., 1997; from 28 randomized controlled trials that compared HRT Clarkson et al., 2001), although this progestin regimen is common (n = 2206) with another agent (n = 1278) for up to 3 years in clinical practice. Otherwise, it was a well-designed and well- (Hemminki and McPherson, 2000). The focus was to compare the executed study, and the only human controlled trial based on rate of cardiovascular events in these controlled trials to the clinical disease end-points to date. It is a landmark study, which reduced cardiovascular event rate in those on HRT noted has sounded an important note of caution for practitioners previously in observational trials (Barrett-Connor and Grady, prescribing HRT in women with known cardiovascular disease.
1998). The pooled data demonstrated an increased cardiovascular The most signi®cant limitation is that the results apply only to the event rate in those on HRT (OR 1.78, 95% CI 0.7±4.52) that was speci®c HRT preparation used and the population studied. The not statistically signi®cant. The ®ndings do not support a ®ndings are not applicable to those without established vascular disease; nor can they be extrapolated to encompass the effects of bene®cial effect of HRT on cardiovascular event rate seen in other estrogen doses and routes of administration or other Other controlled trials focusing on surrogate outcomes are The `ERA' trial, which was published in 2000, compared 3.2 ongoing. The Women's Angiographic Vitamin and Estrogen years of treatment with estrogen (n = 100), combined estrogen + (WAVE) trial, the Women's Estrogen/ Progestin and Lipid- progestin (n = 104) or placebo (n = 105) in post-menopausal Lowering Hormone Atherosclerosis Regression Trial (WELL- women aged 42±80 years with pre-existing coronary disease HART) and the Estrogen and Graft Atherosclerosis Research (Herrington et al., 2000). There was no signi®cant difference in (EAGAR) trial based on angiography in women with bypass the rate of progression of coronary atherosclerosis between the grafts, are all due for completion in the near future should add three groups. Coronary atherosclerosis based on angiographic further to our knowledge base. These studies, along with the data does not necessarily predict the risk of subsequent clinical HERS and ERA studies, involve women with established vascular events, and is not a hard clinical end-point. As with all currently disease. Animal data suggest that estrogen may not have available surrogate markers of vascular disease, it does not re¯ect bene®cial cardiovascular effects in women once atherosclerosis plaque stability and therefore cannot predict those most likely to is established and endothelial damage has occurred (Honore et al., rupture and suffer acute cardiovascular events. However, it does 1996; Hanke et al., 1999). Both human observational data provide a human study similar to the original monkey data (Herrington et al., 2001) and interventional data suggest that this focusing on atherosclerosis development, and the results of this may be the case (Haines et al., 2001), thus highlighting the need study are important for two primary reasons. First, an estrogen- for further investigation into the role of HRT in primary alone arm was included and did not demonstrate bene®ts over combined therapy; second, this study suggested that previous The Women's Health Initiative trial, a primary prevention trial, controlled animal trials focusing on coronary atherosclerosis may is an ongoing study comparing estrogen + progestin to estrogen not be representative of responses in humans.
alone in healthy post-menopausal women aged 55±79 years, with This is also supported by the recent double-blind, placebo- a target enrolment of 27 500 cases. In April 2000, the controlled trial in 664 post-menopausal women with ischaemic investigators informed the participants that `during the ®rst 2 stroke or transient ischaemic attack. Treatment with 1 mg of oral years there was a small increase in the number of heart attacks, 17b-estradiol daily did not alter the risk of subsequent events, strokes and blood clots in women taking active hormones with a total of 99 strokes or deaths in the active and 93 in the compared to inactive pills'. Over time, these differences appeared placebo groups over 2.8 years. The RR was 1.1 (95% CI 0.8±1.4) to diminish. The overall event rate was low, occurring in <1% of women, and the difference between the groups did not reach Further randomized controlled studies focusing on another statistical signi®cance. Yet, the effects of HRT would be surrogate end-point, carotid artery intimal medial thickness consistent with the HERS study, and given that they are seen in (IMT), have also examined the effect of HRT. The ®rst study healthy women, even infrequent events are concerning. A report a reduction in vascular adhesion molecules by endothelial cellsÐ a theoretically bene®cial effect (Simoncini and Genazzani, 2000).
Rabbit studies have suggested a reduction in atherosclerosis development (Zandberg et al., 1998), although a comparative study in the cynomolgus monkey atherosclerosis model demon- strated improved lipids and reduced atherosclerosis with CEE, but not with tibolone. Tibolone reduced HDL, but had no impactÐ either adverse or bene®cialÐon coronary artery atherosclerosis (Clarkson et al., 2001). A small trial in 10 post-menopausal women with angina has demonstrated increased exercise tolerance similar to that observed with estrogen use (Lloyd et al., 1998), whilst a randomized trial based on the effects of tibolone on the surrogate marker, carotid IMT, is pending. There is a suggestion that tibolone may not increase thrombotic risk, although the data are inadequate to draw any such conclusions at present (Winkler et al., 2000). The net clinical signi®cance of these changes in surrogate endpoints remains unknown, and we must await data from controlled trials focusing on de®nitive clinical end-points to establish the role of tibolone in CVD Figure 2. The chemical structures of 17b-estradiol, genestein and daidzein.
Selective ER modulatorsSelective ER modulators (SERMS) are non-steroidal estrogenic scheduled for 2005 will provide more de®nitive data on the compounds with both estrogenic and non-estrogenic actions. They are established for the prevention of breast cancer and for the treatment of osteoporosis (Bush et al., 2001). The data on the cardiovascular effects of SERMS are based on in-vivo animal and human studies, as well as limited data from controlled interven- tional trials on clinical cardiovascular end-points.
Lower-dose regimens (0.3 mg CEE or equivalent) have been the The data on the vascular effects of raloxifene have been focus of much recent research into HRT (Ettinger, 1999). Studies extensively reviewed (Moscarelli and Cox, 2000). Clinical trials have suggested that low-dose HRT can relieve menopausal have demonstrated that SERMs do not change HDL or symptoms and vaginal atrophy (Utian et al., 2001), prevent bone triglyceride levels, but do signi®cantly improve Lp(a) and LDL loss when combined with calcium (Genant et al., 1997; Recker et levels (Walsh et al., 1998; Godsland, 2001). Other circulating markers (including homocysteine levels) each fell, but CRP levels al., 1999) and improve lipid pro®les without inducing endometrial were not changed with raloxifene, compared with falls in hyperplasia (Genant et al., 1997; Lobo et al., 2001). The primary homocysteine and a rise in CRP seen with HRT (Walsh et al., advantage of low-dose regimens is the improved side-effect pro®le and better long-term compliance. A recent analysis from Vascular structural and functional effects have been noted with the 20-year cohort study, The Nurses' Health Study in 70 533 animal data which are suggestive of up-regulation of NO with women, suggested that the cardioprotective effect of 0.3 mg of vasorelaxation and reduced arterial intimal thickening in response CEE was equivalent to that of the higher dose of 0.625 mg to injury. Raloxifene inhibited atherosclerosis in the cholesterol- (Grodstein et al., 2000). This ®nding is encouraging, but is based fed rabbit model (Bjarnason et al., 1997), but not in the monkey on observational data, and once again further clinical trials are model, where no reduction in atherosclerosis was observed required to clarify the role of low-dose HRT regimens in the Human interventional data have been completed with tamox- ifen in a randomized controlled clinical trial in 13 388 women focusing on breast cancer prevention (Reis et al., 2001). No effect The estro-progestogen tibolone is a steroid hormone with a was noted on CVD end-points. Even in a subsequent subgroup progestin-like structure that is converted to estrogenic and analysis for those at high baseline risk akin to the HERS study androgenic derivatives in vivo. It has been shown to improve population, no effect of tamoxifen on cardiovascular events was menopausal symptoms and to improve bone density (although noted (Reis et al., 2001). The ongoing double-blind, placebo- fracture data are still lacking), and it potentially has fewer side controlled Raloxifene Use for the Heart (RUTH) study, focusing effects than conventional HRT (Hammar et al., 1998; Crook, on the effects of raloxifene in 10 101 post-menopausal women 2001). Inadequate human observational data exist on the aged >55 years and with established vascular disease or multiple cardiovascular effects of tibolone. Human studies have provided risk factors, should signi®cantly contribute to our understanding mixed results with reductions in HDL, but also reductions in of the net clinical cardiovascular effects of raloxifene (Mosca et triglycerides and Lp(a) levels, with less effect than conventional al., 2001b). Also, the increase in risk of venous thromboembolic HRT on LDL levels (Godsland, 2001). Animal studies suggested disease appears to be equivalent to that seen with estrogen Table II. The American Heart Association guidelines on HRT and the prevention of cardiovascular disease Secondary preventiond HRT should not be initiated for the secondary prevention of CVD.
d The decision to continue or to stop HRT in women with CVD who have been undergoing long-term HRT should be based on established non-coronary bene®ts and risks and patient preference.
d If a woman develops an acute CVD event or is immobilized while undergoing HRT, it is prudent to consider discontinuance of the HRT, or to consider VTE prophylaxis while she is hospitalized to minimize risk of VTE associated with immobilization. Reinstitution of HRT should be based on established non- coronary bene®ts and risks, as well as patient preference.
Primary preventiond Firm clinical recommendations for primary prevention await the results of ongoing randomized clinical d There are insuf®cient data to suggest that HRT should be initiated for the sole purpose of primary d Initiation and continuation of HRT should be based on established non-coronary bene®ts and risks, possible coronary bene®ts and risks, and patient preference.
From Mosca et al. and the American Heart Association (2001a). Hormone replacement therapy and cardiovascular disease. Circulation, 104, 499±503.
(Ettinger et al., 1999). Given the established prothrombotic risks soybean nor isolated sources of phytoestrogens reduce menopau- of the currently available SERMS, the lack of knowledge on the sal symptoms over placebo therapy (Baber et al., 1999; clinical relevance of changes in surrogate CVD risk factors, and Kotsopoulos et al., 1999; Murkies et al., 2000). In the setting of the apparent neutral cardiovascular effects of tamoxifen in clinical the apparent selectivity and complexity of the endocrine effects of trials, these agents cannot be presently considered as cardiopro- phytoestrogens, it has been suggested that individual effects need to be characterized for each putative estrogenic compound on each estrogenic end-point (Hughes et al., 1991).
Diets rich in phytoestrogens may reduce cardiovascular disease.
Phytoestrogens are a diverse group of plant-derived compounds, Speci®cally, high soy intake is associated with a lower incidence similar to estrogenic steroids (Figure 2) (Davies, 1998).
of cardiovascular disease, and the ingestion of vegetable Iso¯avones are the most common phytoestrogens (Davis et al., proteinÐparticularly soyÐis associated with a reduced risk of 1999), with genistein and diadzein being the most estrogenically coronary heart disease and improved risk factor status active and found in greatest concentrations in soybean (Price and (Aldercreutz, 1998; Davis et al., 1999; Teede et al., 2001c).
Fenwick, 1985). Phytoestrogens have been reported to have both Interventional studies indicate that soy has favourable effects on agonist and antagonist estrogenic effects (Kuiper et al., 1998), lipid pro®les in both primates and humans, and on blood pressure which are not necessarily parallel to those of estrogen. More in humans (Anderson et al., 1995; Davis et al., 1999; Teede et al., recently however, the relative binding af®nities of several 2001c). A meta-analysis of controlled human clinical trials noted phytoestrogens to ERa and ERb have been shown to be that soy protein consumption signi®cantly reduced total choles- signi®cant, especially for ERb. ERb is highly expressed in terol (9.3% decrease, 95% CI 0.35±0.85 mmol/l), LDL-cholester- vascular endothelium and smooth muscle cells; therefore, in ol (12.9% decrease, 95% CI 0.30±0.82 mmol/l) and triglycerides theory phytoestrogens may trigger many of the biological (10.5% decrease, 95% CI 0.003±0.29 mmol/l), with little change responses that are evoked by physiological estrogens (Kuiper et in HDL (Anderson et al., 1995). Responses were related to pre- al., 1998). However, whilst the af®nity of phytoestrogens for ER treatment plasma cholesterol levels. Most research has focused on has been established, ligand±ER interactions are inherently phytoestrogen-rich whole foods or protein isolates, with little complex, and our understanding of the biological potencies of information on concentrated phytoestrogen subfractions in tablet form. However, limited data suggest that isolated phytoestrogens The observed estrogenic effects of phytoestrogens have been are less effective at improving cardiovascular risk factors reviewed extensively (Davis et al., 1999; Murkies et al., 2000). In (Hodgson et al., 1998). Soy supplementation has also been animals, they include reproductive dysfunction, selective neu- associated with reduced atherosclerosis in animals and improved roendocrine effects and effects on sexual development (Davis et vascular function in female monkeys, but not in humans (Honore al., 1999; Murkies et al., 2000). In premenopausal women, et al., 1996; Teede et al., 2001c). The active components of soy menstrual disturbances have been noted, whilst in post-menopau- are not yet established, with potential contributors including sal women improvement in the vaginal maturation index has been vegetable protein, antioxidants and phytoestrogens.
noted (Bickoff et al., 1961; Dalais et al., 1998). Yet more studies Despite observational data on humans and animal and human have failed to show estrogenic effects of dietary soybean in both interventional data focusing on surrogate end-points, once again animals and humans (Baird et al., 1995; Tansey et al., 1998; the net clinical effects of either soy or isolated phytoestrogens on Teede et al., 2001c). Controlled trials have suggested that neither the cardiovascular system remain unknown. Although ongoing studies with combinations of phytoestrogens, antioxidants and atherosclerosis: a randomised controlled trial. Arterioscler. Thromb. Vasc.
micronutrients are awaited with interest, there are currently Anonymous (1994) Randomised comparison of oestrogen versus oestrogen insuf®cient data available to recommend the consumption of plus progestogen hormone replacement therapy in women with isolated supplements for the prevention of CVD. In contrast, the hysterectomy. Medical Research Council's General Practice Research consumption of diverse and balanced diets, which are rich in Framework. Br. Med. J., 312, 473±478.
foods containing many nutrients, including antioxidants and Anonymous (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The postmenopausal phytoestrogens, can be safely recommended (Teede and estrogen/progestin interventions (PEPI) trial. JAMA, 273, 199±208.
Anonymous (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 352, 854± Baber, R.J., Templeman, C., Morton, T., Kelly, G.E. and West, L. (1999) CVD is the number one killer of both men and women in Western Randomized placebo-controlled trial of an iso¯avone supplement and countries. Prevention strategies are very effective in reducing the menopausal symptoms in women. Climacteric, 2, 85±92.
Baird, D.D., Umbach, D.M., Lansdell, L., Hughes, C.L., Setchell, K.D., burden of CVD. Well-established prevention strategies including Weinberg, C.R., Haney, A.F., Wilcox, A.J. and Mclachlan, J.A. (1995) lifestyle modi®cations and speci®cally targeted pharmacological Dietary intervention study to assess estrogenicity of dietary soy among treatments remain under-utilized, especially in women.
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Submitted on December 11, 2001; accepted on February 21, 2002


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